Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder with onset generally in midlife. HD is characterized by chorea, dementia, and neuropsychiatric problems. The mutation lies in the expansion of a polymorphic CAG repeat resulting in greater than normal length of polyglutamines in the N-terminal end of the HD gene product (huntingtin) which is of unknown function. We have created mouse models for HD that recapitulates features of behavioral abnormalities and neuropathological changes inherent in the human disease. These mice carrying the repeat expansions show progressive behavior going from hyperkinesia to hypokinesia and akinesia. Pathologically, neurons show early dendritic changes cumlminating in apoptotic changes and cell loss. We have identified morphological changes in affected neurons of these mice that mark early events of pathogenesis and these changes are supported independently by molecular and biochemical approaches using cDNA microarrays and immunocytochemical stains for vesicular proteins and cytoskeleton. The interplay of mutant huntingtin with these proteins and how these interactions could lead to neurodegenertaive changes are the subject of intense investigation by this group. These studies will lead to a better understanding of brain function as it relates to cognition, emotions, and neuronal survival; and may lead to better therapeutic regimens for HD and other degenerative disorders of the brain.